PROJECT SUMMARY/ABSTRACT Interactions between mitochondrial (mtDNA) and nuclear (nDNA) genomes are essential for maintaining mitochondrial and cellular functions. However, an age- and disease-associated increase of heteroplasmic mtDNA (the presence of different mtDNA haplotypes) creates an inter-genomic mismatch that perturbs mitonuclear interaction efficiency. Disrupted mitonuclear interaction results in mitochondrial dysfunction, reduced organismal fitness, and initiation of various stress that has been associated with a plethora of many human diseases, such as Huntington's disease, Leber's hereditary optic neuropathy, and type 2 diabetes mellitus. In response to disrupted mitonuclear interactions, cells activate stress response pathways to remodel gene expression and metabolism, thereby maintaining mitochondrial function and alleviating cellular stress. However, a detailed molecular understanding of mitonuclear mechanisms linking activation of stress response pathways for maintaining mitochondrial function and stress resistance has been understudied, representing a significant knowledge gap. I hypothesize that distinct mismatched mitonuclear genomes maintain coordination of mitochondrial status with various stress response pathways to alleviate harmful consequences of suboptimal mitonuclear interactions. To test this hypothesis, we developed a novel yeast mitonuclear exchange model (cytoductants) by combining more than 100 mtDNA genotypes onto the same nDNA genetic background, thereby generating an elegant system with various degrees of perturbation in mitonuclear interaction and altered mitochondrial function. Overall, the main goal of our research is to mechanistically understand how perturbations in mitonuclear interaction are transduced into biological effects. My laboratory will build and sustain three research projects to accomplish this goal. We will first test the hypothesis that understanding mitonuclear communication at molecular level will uncover distinct mitonuclear responses to perturbed mitonuclear interactions. (Project 1). Secondly, we will identify the crosstalk between stress response pathways and their downstream effectors in protecting cells from various stress under the condition of perturbed mitonuclear interaction. Further, we will determine whether a specific type of stressor determines the specificity of the response or not (Project 2). Finally, with an innovative cell engineering approach, we will investigate the hypothesis that balancing cellular energy hemostasis can mitigate the effect of disrupted mitonuclear interaction (Project 3). The proposed research is significant because it will uncover how cells respond to disrupted mitonuclear interactions to maintain cellular homeostasis. Since many mitochondrial diseases are carried in heteroplasmy, this basic research into the maintenance of mitonuclear interaction will likely identify modulators of efficient mitochondrial interaction. It might be targeted pharmacolo...